The major accomplishment of the GPB has been the transformation of the research group from its previous focus on short-term pharmacologic challenge studies and small clinical trials with AD subjects to its current focus on longitudinal studies of "at risk" subjects, AD patients, and elderly bereaved subjects. In addition, the Branch has developed from scratch, under the leadership of Dr. Cohen, a small but significant group to incorporate imaging measures in the above studies. This review will allow us the opportunity to present the earliest unpublished data from these longitudinal studies. One such finding involves the decrease of b-amyloid in CSF in APO E4 positive controls who are "at risk" for AD by virtue of their increasing age and positive family history. We will also describe the initial significant finding from our Neuroimaging Section where the APO E4 positive individuals have been shown to lose hippocampal volume on repeat 1.5 tesla MRI scans at a faster annual rate than APO E4 negative individuals, despite the fact that there are no easily discriminable cognitive or other clinical abnormalities in either group. These are two key findings that will serve as a focus for our ongoing longitudinal study over the next several years. One of the first publications to emerge from this new biomarkers approach describes the longitudinal stability of CSF tau protein in a group of mild-to-moderately effected AD subjects (Sunderland et al, 1999). This work resulted from a collaboration between the NIMH GPB and Athena Diagnostics. This is one of many collaborations that allow the Branch to expand its work beyond the clinical and neuroimaging expertise of its core team without the need to develop a larger laboratory presence. These collaborations range from California to Massachusetts in the U.S. and include Finland, England, and Germany internationally. Perhaps the most interesting collaboration involves the use of high-throughput, exquisitely sensitive 2D gel electrophoresis techniques which provide quantitative data reflecting the relative up- and down-regulation of proteins in human CSF. In this study, we are generating cross-sectional data on over 1200 proteins in groups of AD and "at risk" subjects. Perhaps more importantly, we are generating longitudinal data in both these groups through repeat CSF collections that will allow us to track protein changes from the presymptomatic state to end-stage Alzheimer's disease. In this way, we will be developing potential targets for later therapeutic trials that may facilitate the eventual prophylactic treatment of this devastating disease.